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1.
J Med Life ; 14(5): 700-709, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35027974

RESUMO

The main aim of this study is to systematically record Cerebrolysin treatment modalities and concomitant medication, according to local standards, in patients with moderate to severe neurological deficits after acute ischemic stroke and to assess the impact of these parameters on therapy outcome during early rehabilitation (day 21) and on day 90. An open observational treatment design based on the principles of high-quality comparative effectiveness research (HQCER) has been chosen to capture the therapies as applied in real-world clinical practice. HQCER opens a new horizon for strengthening the validity of the results from observational trials, thereby enhancing the associated level of evidence. Rigorous pre-specification of analytical procedures and tight risk-based centralized monitoring were additional measures to improve the impact of the observational approach. The value for real-world studies has become obvious, and such studies based on comparative effectiveness designs supplement the classical study designs by enabling the inclusion of larger proband numbers and more statistical reliability for practical use.


Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Humanos , Reprodutibilidade dos Testes , Projetos de Pesquisa , Acidente Vascular Cerebral/tratamento farmacológico
2.
BMC Neurosci ; 15: 90, 2014 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-25047000

RESUMO

BACKGROUND: Alzheimer's Disease (AD) and Fronto temporal lobar dementia (FTLD) are common causes of dementia in the aging population for which limited therapeutical options are available. These disorders are associated with Tau accumulation. We have previously shown that Cerebrolysin™ (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the behavioral deficits and neuropathological alterations in amyloid precursor protein (APP) transgenic (tg) mouse model of AD by reducing hyper-phosphorylated Tau. CBL has been tested in clinical trials for AD, however it's potential beneficial effects in FTLD are unknown. For this purpose we sought to investigate the effects of CBL in a tg model of tauopathy. Accordingly, double tg mice expressing mutant Tau under the mThy-1 promoter and GSK3ß (to enhance Tau phosphorylation) were treated with CBL and evaluated neuropathologically. RESULTS: Compared to single Tau tg mice the Tau/GSK3ß double tg model displayed elevated levels of Tau phosphorylation and neurodegeneration in the hippocampus. CBL treatment reduced the levels of Tau phosphorylation in the dentate gyrus and the degeneration of pyramidal neurons in the temporal cortex and hippocampus of the Tau/GSK3ß double tg mice. Interestingly, the Tau/GSK3ß double tg mice also displayed elevated levels of Dynamin-related protein-1 (Drp-1), a protein that hydrolyzes GTP and is required for mitochondrial division. Ultrastructural analysis of the mitochondria in the Tau/GSK3ß double tg mice demonstrated increased numbers and fragmentation of mitochondria in comparison to non-tg mice. CBL treatment normalized levels of Drp-1 and restored mitochondrial structure. CONCLUSIONS: These results suggest that the ability of CBL to ameliorate neurodegenerative pathology in the tauopathy model may involve reducing accumulation of hyper-phosphorylated Tau and reducing alterations in mitochondrial biogenesis associated with Tau.


Assuntos
Aminoácidos/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Fármacos Neuroprotetores/farmacologia , Tauopatias/tratamento farmacológico , Tauopatias/patologia , Envelhecimento , Animais , Modelos Animais de Doenças , Dinaminas/metabolismo , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Fosforilação/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/patologia , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/patologia , Proteínas tau/genética , Proteínas tau/metabolismo
3.
J Clin Endocrinol Metab ; 95(3): 1469-72, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20130071

RESUMO

CONTEXT: Pheochromocytomas and paragangliomas are genetically heterogeneous tumors of neural crest origin. Approximately half of these tumors activate a pseudohypoxic transcription response, which is due in a minority of the cases to germline mutations of the VHL gene or the genes encoding subunits of the metabolic enzyme succinate dehydrogenase (SDH), SDHB, SDHC, or SDHD. However, the genetic basis of the hypoxic-like profile of the remaining tumors is undetermined. Mutations in genes involved in the energy metabolism, isocitrate dehydrogenase 1 (IDH1) and -2 (IDH2) and SDHAF2, a component of SDH, can mimic a pseudohypoxic state. DESIGN: We examined the sequence spanning the mutation-susceptible codons 132 of IDH1 and 172 of IDH2, and the entire coding region of SDHAF2, in 104 pheochromocytomas and paragangliomas, including tumors with a pseudohypoxic expression profile. RESULTS: We did not find mutations in IDH1, IDH2, or SDHAF2 in any of the tumors in this cohort. CONCLUSION: Conserved residues of IDH1 and IDH2 or the SDHAF2 gene are not frequently mutated in pheochromocytomas and paragangliomas. The molecular basis for activation of a hypoxic response in the majority of tumors without VHL or SDH mutations remains to be defined.


Assuntos
Hipóxia Celular/genética , Isocitrato Desidrogenase/genética , Proteínas Mitocondriais/genética , Paraganglioma/genética , Neoplasias Abdominais/genética , Neoplasias das Glândulas Suprarrenais/genética , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Mutação/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
5.
Anticancer Res ; 25(6B): 4225-30, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16309220

RESUMO

BACKGROUND: Medullary thyroid carcinoma (MTC) is a calcitonin-producing tumor of the parafollicular C-cells, accounting for 5-10% of all thyroid tumors. To date, the only effective treatment is the early and total surgical removal of all neoplastic tissue. As the prognosis of patients with advanced MTC, unresectable or distant metastases is poor, and chemotherapy or irradiation is of no significant value, alternative strategies have been sought. MATERIALS AND METHODS: A promising treatment approach for human MTC, that has already been introduced at our facility, is based on vaccination with autologous dendritic cells (DCs). Strong evidence that vaccination with autologous tumor lysate-pulsed DCs induces a specific immune response in vivo has been provided. However, the therapeutic success of this approach is sometimes critically limited by the small amount of tumor material available, especially from patients operated at an early tumor stage. Thus, it would be to the best advantage to have sufficient amounts of autologous tumor cells available for DC pulsing. RESULTS: A method to generate viable autologous tumor cell cultures from a variety of MTC tissue samples, even when the sample size is small, has been successfully established. These cell lines maintain their neuroendocrine phenotype. In addition, it can be shown that these cells also display the biological features of neuroendocrine tumor cells at the molecular level. CONCLUSION: The unlimited availability of these MTC cell lines makes it possible to specify cancerogenesis of MTC. In addition, the availability of sufficient amounts of tumor lysate from these cell lines offers the advantage of prolonged immunotherapy. Finally, these cell lines could be elegantly used as read-out system to monitor the in vivo immune response during immunotherapy with DC cell-based vaccination in patients suffering from MTC.


Assuntos
Vacinas Anticâncer/imunologia , Carcinoma Medular/imunologia , Carcinoma Medular/terapia , Imunoterapia Adotiva/métodos , Neoplasias da Glândula Tireoide/imunologia , Neoplasias da Glândula Tireoide/terapia , Animais , Vacinas Anticâncer/uso terapêutico , Carcinoma Medular/patologia , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias da Glândula Tireoide/patologia
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